Project Summary/Abstract Alcoholism and depression often co-occur in humans, but it has been difficult to find a single treatment which is effective against both conditions. This comorbid condition is frequently observed following impulsive binge alcohol consumption, as well as in compulsive drinking in humans. The primary objective of the present proposal is to identify effective compounds at the preclinical level that may serve as prototypes for further evaluation of clinical efficacy in treating the comorbid condition. To accomplish this, a series of triple monoamine uptake inhibitors [TUIs] [e.g., DOV 216,303, DOV 21,947, and DOV 102,677], which have been successfully tested in Phase I studies for depression with published preclinical-antidepressant [AD] efficacy, will be evaluated. The first aim will test the hypothesis that orally-administered TUIs can effectively attenuate excessive alcohol drinking in the binge and prolonged repeated alcohol deprivation [PRAD] models using the alcohol-preferring [P] rat. Initial studies will employ DOV 102,677 [our lead compound], recently shown to reduce limited alcohol responding for six days after a single administration. It is hypothesized that acute treatment for binge drinking, and chronic treatment for PRAD drinking, will selectively reduce intake in both models. The second aim will test the hypothesis that TUIs will effectively attenuate the negative affective states [e.g., withdrawal symptomatology], characterized by reductions in pleasure [i.e., anhedonia] and increased immobility [i.e., indicative of depressive-like behaviors] following alcohol-induced abstinence from binge and PRAD drinking. Negative affective states will be inferred using the intracranial self-stimulation [ICSS] and forced swim test [FST] models. We hypothesize that both acute and chronic DOV treatments will attenuate the negative affective states associated with alcohol-induced abstinence from the two heavy drinking models. Aim 3 will test the hypothesis that similar neurobiological substrates mediate alcohol dependence and the negative affective states associated with binge drinking within the extended amygdala [EA] [i.e., bed nucleus of the stria terminalis (BST); central nucleus of the amygdala (CeA); shell of the nucleus accumbens (nAcc)]; and medial prefrontal cortex (mPfc). To evaluate this hypothesis, site-specific microinjection of our lead TUI [DOV 102, 677] will be given in the EA loci and mPfc. However, because little if any data are available on the precise brain substrates which regulate the actions of TUIs, we will initially employ the c-fos technology in nave P rats to delineate multiple CNS loci which may mediate the actions of DOV 102, 677. These studies should identify effective compounds at the preclinical level which may serve as prototypes for further evaluation of clinical efficacy in treating comorbid alcoholism and depression, as well as shed light on the neurobiological commonalities which regulate the two conditions.